Dr. Sweatt received his bachelor's degree in Chemistry from the University of South Alabama and his Ph.D. in Pharmacology from Vanderbilt University. He did a post-doctoral Fellowship at the Columbia University Center for Neurobiology and Behavior, working on memory mechanisms in the laboratory of Nobel laureate Eric Kandel. From 1989 until 2006 he was in the Department of Neuroscience at Baylor College of Medicine, rising through the ranks to Professor. At the University of Alabama at Birmingham, he serves as the Director of the Evelyn F. McKnight Brain Research Institute and is the Evelyn F. McKnight Endowed Chair of the Department of Neurobiology. His research focuses on the signal-transduction mechanisms operating to control gene transcription in learning and memory. In addition, his research program also investigates mechanisms of learning and memory disorders, such as mental retardation and aging-related memory dysfunction. He is an associate editor for the Journal of Neuroscience and other scientific journals, and the author of a textbook, Mechanisms of Memory.

Research Interests: Signal Transduction Mechanisms in Learning and Memory

Our interest is in understanding the biochemical mechanisms underlying learning and memory. One of the major advances in neurobiology in the last century was the formulation of the general theory that changes in synaptic connections between neurons underlie information storage in the CNS. From our perspective one powerful offshoot of this general theory is that it allows a reductionist approach, that is, that by studying the mechanisms of long-lasting synaptic plasticity in vitro we can generate insights into the mechanisms of learning and memory in vivo. Using this rationale, for the last decade my laboratory has been investigating the biochemical mechanisms subserving the induction and maintenance of long-term potentiation in the hippocampus. In general our focus has been on signal transduction, with a particular emphasis on the role of protein kinases in LTP. Our work, and that of many other labs, has indicated that four protein kinases play particularly prominent roles in LTP: PKA, PKC, CaMKII, and erk MAPK. By and large PKC and CaMKII have achieved notoriety for their roles as molecular information storage devices; autonomously active forms of these kinases subserve the maintenance of early LTP. In contrast, PKA and MAPK appear predominantly to be involved in triggering the induction of early and late stages of LTP. While we have investigated all of these protein kinase cascades over the last decade, of late we have focused most of our effort on studies of the MAPK and PKC cascades.

A role for MAPK in synaptic plasticityOur recent discovery of a role for MAPK in LTP has been somewhat of a watershed event for us, and has led us to begin to investigate in detail the role of this signal transduction cascade in the hippocampus. We initially observed that MAPK is activated in an NMDA receptor-dependent fashion in LTP, and that this activation is necessary for LTP induction. Recently we have focused on two issues arising from these observations; how is MAPK regulated in the hippocampus and what are its downstream effectors. We have discovered that MAPK is regulated by both the PKA and PKC cascades, and via these pathways is regulated by a variety of neuromodulatory neurotransmitter receptors in the hippocampus. Thus MAPK appears to serve an important role as a signal integrator in the hippocampus. Furthermore, we have found that MAPK is a critical regulator of both CREB phosphorylation and K-channel phosphorylation in the hippocampus, indicating a broad variety in the types of cellular responses that may be regulated by MAPK.

We are building on these findings through three avenues of experimentation at present. First, we are using knockout animals for specific isoforms of MAPK to test our hypothesis that p42 MAPK (erk2) is particularly important for the biochemical and physiologic roles of MAPK in the hippocampus. Second, we are evaluating new effectors of MAPK, such as transcription factors and other regulators of gene expression. Third, we are using phospho-site specific antibodies we developed in order to determine if MAPK regulates Kv4.2 phosphorylation in LTP and in response to neuromodulatory neurotransmitter stimulation.

Transitioning from synaptic plasticity to behavior While we have made great progress in understanding the role of signal transduction cascades in LTP, the broader goal of my research is to understand learning and memory in the animal. Our studies in this area are guided by the general hypothesis that biochemical mechanisms for LTP will be valid predictors for mechanisms for learning and memory in vivo. We are approaching this problem in two ways, by testing two specific predictions of our overall hypothesis. First, we are determining if the LTP-associated signal transduction mechanisms are activated in vivo when the animal learns. Second, we are determining if blocking these signal transduction cascades, using pharmacologic and genetic approaches, leads to learning and memory deficits in the behaving animal. We use a variety of behavioral paradigms in our whole-animal studies, but have emphasized the cued and contextual variants of fear conditioning because of the robustness of the learning and the relatively well-defined anatomical substrates of the learning. For our biochemical studies in vivo we are using various phospho-site specific antibodies that we and others have developed, which selectively tag activated forms of PKC, MAPK, CaMKII, and CREB. Our studies to date have used Western blotting procedures to quantitate anatomical subregion-specific changes in phosphorylation of these molecules. One particularly exciting new avenue we are pursuing is utilizing these same antibodies in immunohistochemistry procedures, so that we will be able to obtain much more precise anatomical localization of biochemical changes in the animal's CNS that result from learning. We are of course coupling our behavioral and biochemical studies in vivo with the kinase isoform-selective knockouts described above, in order to investigate the necessity of these specific enzyme species for both learning and learning-associated biochemical changes.

Potential insights into hippocampal pathologiesWe also are interested in using what we have learned about hippocampal synaptic plasticity to generate insights into human pathological conditions. With this in mind, we have been using the kainate model of epilepsy to investigate the potential role of MAPK in epileptogenesis. In our pilot studies we have observed striking hippocampal MAPK activation, CREB phosphorylation, and K-channel phosphorylation after kainate injection. We will be pursuing these observations using pharmacologic and knockout manipulations to determine if these changes are causally related to seizure generation in the animal. A second major line of investigation is related to Alzheimer's Disease. We utilize transgenic (mutant APP and presenilin) mouse models for AD to determine if hippocampal signal transduction mechanisms and transcriptional regulation mechanisms are deranged in this learning-deficient mouse strain.

a7 Nicotinic Acetylcholine Receptors in Aging-related Memory LossAnother of our recent projects involves the alpha7 nicotinic acetylcholine receptor which is highly expressed in hippocampus and in cholinergic projection neurons from the basal forebrain. These structures are especially interesting to our lab since they are particularly vulnerable in aging related memory loss. Also of interest in our research, elevated levels of -amyloid peptide have been shown in previous studies to lead to hippocampal dysfunction, but the mechanism is not known. We are testing the hypothesis that -amyloid peptide directly interacts with the alpha7 nicotinic acetylcholine receptor by evaluating the effects of -amyloid peptide on hippocampal physiology and testing the role of the alpha 7 nicotinic receptor in these effects.

Mental Retardation SyndromesOver the past few years we and several other groups have begun using a new approach to bridge the gap between specific molecules and human cognition. The essence of this approach is to identify naturally occurring human genetic mutations that result in mental retardation/learning disorders and use knockout and transgenic mouse models to generate insights into the underlying molecular and cellular basis for the defect. The rationale is that this will give insights into the humans who are missing the same gene and hence give insights into the molecular neurobiology of human cognitive processing. We have used this approach, in collaboration with several investigators across the country, to study mouse models including the mouse model for Angelman syndrome, Rett Syndrome and Fragile X syndromes. The characterization we perform on these mouse models consists of electrophysiological, biochemical and behavioral assessments which lead to a greater knowledge of the causes and implications of these disorders in humans.

Overview and Future DirectionsIn broad terms, our future scientific goal is to capitalize upon our recent insights into the signal transduction mechanisms operating in hippocampal synaptic plasticity; we will do this by utilizing a multidisciplinary approach combining in vitro biochemistry, electrophysiology, immunohistochemistry, and behavioral assays. We will use both pharmacologic and genetic experimental manipulations in order to investigate both the molecular basis of normal learning and the biochemical derangements that underlie pathological conditions affecting learning and memory.